A Likelihood-Based Approach with Shared Latent Random Parameters for the Longitudinal Binary and Informative Censoring Processes

Longitudinal studies with binary outcomes characterized by informative right censoring are commonly encountered in clinical, basic, behavioral, and health sciences. Approaches developed to analyze data with binary outcomes were mainly tailored to clustered or longitudinal data with missing completely at random or at random. Studies that focused on informative right censoring with binary outcomes are characterized by their imbedded computational complexity and difficulty of implementation. Here we present a new maximum likelihood-based approach with repeated binary measures modeled in a generalized linear mixed model as a function of time and other covariates. The longitudinal binary outcome and the censoring process determined by the number of times a subject is observed share latent random variables (random intercept and slope) where these subject-specific random effects are common to both models. A simulation study and sensitivity analysis were conducted to test the model under different assumptions and censoring settings. Our results showed accuracy of the estimates generated under this model when censoring was fully informative or partially informative with dependence on the slopes. A successful implementation was undertaken on a cohort of renal transplant patients with blood urea nitrogen as a binary outcome measured over time to indicate normal and abnormal kidney function until the emanation of graft rejection that eventuated in informative right censoring. In addition to its novelty and accuracy, an additional key feature and advantage of the proposed model is its viability of implementation on available analytical tools and widespread application on any other longitudinal dataset with informative censoring.

     

Normal frailty probit model for clustered interval‐censored failure time data

Clustered interval‐censored data commonly arise in many studies of biomedical research where the failure time of interest is subject to interval‐censoring and subjects are correlated for being in the same cluster. A new semiparametric frailty probit regression model is proposed to study covariate effects on the failure time by accounting for the intracluster dependence. Under the proposed normal frailty probit model, the marginal distribution of the failure time is a semiparametric probit model, the regression parameters can be interpreted as both the conditional covariate effects given frailty and the marginal covariate effects up to a multiplicative constant, and the intracluster association can be summarized by two nonparametric measures in simple and explicit form. A fully Bayesian estimation approach is developed based on the use of monotone splines for the unknown nondecreasing function and a data augmentation using normal latent variables. The proposed Gibbs sampler is straightforward to implement since all unknowns have standard form in their full conditional distributions. The proposed method performs very well in estimating the regression parameters as well as the intracluster association, and the method is robust to frailty distribution misspecifications as shown in our simulation studies. Two real‐life data sets are analyzed for illustration.     

A Bayesian approach for joint modeling of cluster size and subunit-specific outcomes

In applications that involve clustered data, such as longitudinal studies and developmental toxicity experiments, the number of subunits within a cluster is often correlated with outcomes measured on the individual subunits. Analyses that ignore this dependency can produce biased inferences. This article proposes a Bayesian framework for jointly modeling cluster size and multiple categorical and continuous outcomes measured on each subunit. We use a continuation ratio probit model for the cluster size and underlying normal regression models for each of the subunit-specific outcomes. Dependency between cluster size and the different outcomes is accommodated through a latent variable structure. The form of the model facilitates posterior computation via a simple and computationally efficient Gibbs sampler. The approach is illustrated with an application to developmental toxicity data, and other applications, to joint modeling of longitudinal and event time data, are discussed.     

Weighted Estimation of the Accelerated Failure Time Model in the Presence of Dependent Censoring

Independent censoring is a crucial assumption in survival analysis. However, this is impractical in many medical studies, where the presence of dependent censoring leads to difficulty in analyzing covariate effects on disease outcomes. The semicompeting risks framework offers one approach to handling dependent censoring. There are two representative estimators based on an artificial censoring technique in this data structure. However, neither of these estimators is better than another with respect to efficiency (standard error). In this paper, we propose a new weighted estimator for the accelerated failure time (AFT) model under dependent censoring. One of the advantages in our approach is that these weights are optimal among all the linear combinations of the previously mentioned two estimators. To calculate these weights, a novel resampling-based scheme is employed. Attendant asymptotic statistical results for the estimator are established. In addition, simulation studies, as well as an application to real data, show the gains in efficiency for our estimator.     

Bayesian Latent Factor Regression for Functional and Longitudinal Data

Summary In studies involving functional data, it is commonly of interest to model the impact of predictors on the distribution of the curves, allowing flexible effects on not only the mean curve but also the distribution about the mean. Characterizing the curve for each subject as a linear combination of a high‐dimensional set of potential basis functions, we place a sparse latent factor regression model on the basis coefficients. We induce basis selection by choosing a shrinkage prior that allows many of the loadings to be close to zero. The number of latent factors is treated as unknown through a highly‐efficient, adaptive‐blocked Gibbs sampler. Predictors are included on the latent variables level, while allowing different predictors to impact different latent factors. This model induces a framework for functional response regression in which the distribution of the curves is allowed to change flexibly with predictors. The performance is assessed through simulation studies and the methods are applied to data on blood pressure trajectories during pregnancy.     

Joint analysis of longitudinal data with informative right censoring

Longitudinal data arise when subjects are followed over a period of time. A commonly encountered complication in the analysis of such data is the variable length of follow-up due to right censorship. This can be further exacerbated by the possible dependency between the censoring time and the longitudinal measurements. This article proposes a combination of a semiparametric transformation model for the censoring time and a linear mixed effects model for the longitudinal measurements. The dependency is handled via latent variables which are naturally incorporated. We show that the likelihood function has an explicit form and develops a two-stage estimation procedure to avoid direct maximization over a high-dimensional parameter space. The resulting estimators are shown to be consistent and asymptotically normal, with a closed form for the variance-covariance matrix that can be used to obtain a plug-in estimator. Finite sample performance of the proposed approach is assessed through extensive simulations. The method is applied to renal disease data.     

Cox regression model with randomly censored covariates

This paper deals with a Cox proportional hazards regression model, where some covariates of interest are randomly right‐censored. While methods for censored outcomes have become ubiquitous in the literature, methods for censored covariates have thus far received little attention and, for the most part, dealt with the issue of limit‐of‐detection. For randomly censored covariates, an often‐used method is the inefficient complete‐case analysis (CCA) which consists in deleting censored observations in the data analysis. When censoring is not completely independent, the CCA leads to biased and spurious results. Methods for missing covariate data, including type I and type II covariate censoring as well as limit‐of‐detection do not readily apply due to the fundamentally different nature of randomly censored covariates. We develop a novel method for censored covariates using a conditional mean imputation based on either Kaplan–Meier estimates or a Cox proportional hazards model to estimate the effects of these covariates on a time‐to‐event outcome. We evaluate the performance of the proposed method through simulation studies and show that it provides good bias reduction and statistical efficiency. Finally, we illustrate the method using data from the Framingham Heart Study to assess the relationship between offspring and parental age of onset of cardiovascular events.     

Regression analysis when covariates are regression parameters of a random effects model for observed longitudinal measurements

We consider regression analysis when covariate variables are the underlying regression coefficients of another linear mixed model. A naive approach is to use each subject's repeated measurements, which are assumed to follow a linear mixed model, and obtain subject-specific estimated coefficients to replace the covariate variables. However, directly replacing the unobserved covariates in the primary regression by these estimated coefficients may result in a significantly biased estimator. The aforementioned problem can be evaluated as a generalization of the classical additive error model where repeated measures are considered as replicates. To correct for these biases, we investigate a pseudo-expected estimating equation (EEE) estimator, a regression calibration (RC) estimator, and a refined version of the RC estimator. For linear regression, the first two estimators are identical under certain conditions. However, when the primary regression model is a nonlinear model, the RC estimator is usually biased. We thus consider a refined regression calibration estimator whose performance is close to that of the pseudo-EEE estimator but does not require numerical integration. The RC estimator is also extended to the proportional hazards regression model. In addition to the distribution theory, we evaluate the methods through simulation studies. The methods are applied to analyze a real dataset from a child growth study.     

Analysis of failure time data with multilevel clustering, with application to the child vitamin a intervention trial in Nepal

We consider the problem of estimating covariate effects in the marginal Cox proportional hazard model and multilevel associations for child mortality data collected from a vitamin A supplementation trial in Nepal, where the data are clustered within households and villages. For this purpose, a class of multivariate survival models that can be represented by a functional of marginal survival functions and accounts for hierarchical structure of clustering is exploited. Based on this class of models, an estimation strategy involving a within-cluster resampling procedure is proposed, and a model assessment approach is presented. The asymptotic theory for the proposed estimators and lack-of-fit test is established. The simulation study shows that the estimates are approximately unbiased, and the proposed test statistic is conservative under extremely heavy censoring but approaches the size otherwise. The analysis of the Nepal study data shows that the association of mortality is much greater within households than within villages.     

Latent transition regression for mixed outcomes

Health status is a complex outcome, often characterized by multiple measures. When assessing changes in health status over time, multiple measures are typically collected longitudinally. Analytic challenges posed by these multivariate longitudinal data are further complicated when the outcomes are combinations of continuous, categorical, and count data. To address these challenges, we propose a fully Bayesian latent transition regression approach for jointly analyzing a mixture of longitudinal outcomes from any distribution. Health status is assumed to be a categorical latent variable, and the multiple outcomes are treated as surrogate measures of the latent health state, observed with error. Using this approach, both baseline latent health state prevalences and the probabilities of transitioning between the health states over time are modeled as functions of covariates. The observed outcomes are related to the latent health states through regression models that include subject-specific effects to account for residual correlation among repeated measures over time, and covariate effects to account for differential measurement of the latent health states. We illustrate our approach with data from a longitudinal study of back pain.     

Double Inverse‐Weighted Estimation of Cumulative Treatment Effects Under Nonproportional Hazards and Dependent Censoring

Summary In medical studies of time‐to‐event data, nonproportional hazards and dependent censoring are very common issues when estimating the treatment effect. A traditional method for dealing with time‐dependent treatment effects is to model the time‐dependence parametrically. Limitations of this approach include the difficulty to verify the correctness of the specified functional form and the fact that, in the presence of a treatment effect that varies over time, investigators are usually interested in the cumulative as opposed to instantaneous treatment effect. In many applications, censoring time is not independent of event time. Therefore, we propose methods for estimating the cumulative treatment effect in the presence of nonproportional hazards and dependent censoring. Three measures are proposed, including the ratio of cumulative hazards, relative risk, and difference in restricted mean lifetime. For each measure, we propose a double inverse‐weighted estimator, constructed by first using inverse probability of treatment weighting (IPTW) to balance the treatment‐specific covariate distributions, then using inverse probability of censoring weighting (IPCW) to overcome the dependent censoring. The proposed estimators are shown to be consistent and asymptotically normal. We study their finite‐sample properties through simulation. The proposed methods are used to compare kidney wait‐list mortality by race.     

Latent variable models for longitudinal data with multiple continuous outcomes

Multiple outcomes are often used to properly characterize an effect of interest. This paper proposes a latent variable model for the situation where repeated measures over time are obtained on each outcome. These outcomes are assumed to measure an underlying quantity of main interest from different perspectives. We relate the observed outcomes using regression models to a latent variable, which is then modeled as a function of covariates by a separate regression model. Random effects are used to model the correlation due to repeated measures of the observed outcomes and the latent variable. An EM algorithm is developed to obtain maximum likelihood estimates of model parameters. Unit-specific predictions of the latent variables are also calculated. This method is illustrated using data from a national panel study on changes in methadone treatment practices.     

Estimation of integrated transition hazards and stage occupation probabilities for non-Markov systems under dependent censoring

We propose nonparametric estimators of the stage occupation probabilities and transition hazards for a multistage system that is not necessarily Markovian, using data that are subject to dependent right censoring. We assume that the hazard of being censored at a given instant depends on a possibly time-dependent covariate process as opposed to assuming a fixed censoring hazard (independent censoring). The estimator of the integrated transition hazard matrix has a Nelson-Aalen form where each of the counting processes counting the number of transitions between states and the risk sets for leaving each stage have an IPCW (inverse probability of censoring weighted) form. We estimate these weights using Aalen's linear hazard model. Finally, the stage occupation probabilities are obtained from the estimated integrated transition hazard matrix via product integration. Consistency of these estimators under the general paradigm of non-Markov models is established and asymptotic variance formulas are provided. Simulation results show satisfactory performance of these estimators. An analysis of data on graft-versus-host disease for bone marrow transplant patients is used as an illustration.     

Bayesian models for multivariate current status data with informative censoring

Multivariate current status data, consist of indicators of whether each of several events occur by the time of a single examination. Our interest focuses on inferences about the joint distribution of the event times. Conventional methods for analysis of multiple event-time data cannot be used because all of the event times are censored and censoring may be informative. Within a given subject, we account for correlated event times through a subject-specific latent variable, conditional upon which the various events are assumed to occur independently. We also assume that each event contributes independently to the hazard of censoring. Nonparametric step functions are used to characterize the baseline distributions of the different event times and of the examination times. Covariate and subject-specific effects are incorporated through generalized linear models. A Markov chain Monte Carlo algorithm is described for estimation of the posterior distributions of the unknowns. The methods are illustrated through application to multiple tumor site data from an animal carcinogenicity study.     

Principal stratification in causal inference

Many scientific problems require that treatment comparisons be adjusted for posttreatment variables, but the estimands underlying standard methods are not causal effects. To address this deficiency, we propose a general framework for comparing treatments adjusting for posttreatment variables that yields principal effects based on principal stratification. Principal stratification with respect to a posttreatment variable is a cross-classification of subjects defined by the joint potential values of that posttreatment variable tinder each of the treatments being compared. Principal effects are causal effects within a principal stratum. The key property of principal strata is that they are not affected by treatment assignment and therefore can be used just as any pretreatment covariate. such as age category. As a result, the central property of our principal effects is that they are always causal effects and do not suffer from the complications of standard posttreatment-adjusted estimands. We discuss briefly that such principal causal effects are the link between three recent applications with adjustment for posttreatment variables: (i) treatment noncompliance, (ii) missing outcomes (dropout) following treatment noncompliance. and (iii) censoring by death. We then attack the problem of surrogate or biomarker endpoints, where we show, using principal causal effects, that all current definitions of surrogacy, even when perfectly true, do not generally have the desired interpretation as causal effects of treatment on outcome. We go on to forrmulate estimands based on principal stratification and principal causal effects and show their superiority.     

Goodness-of-fit tests in proportional hazards models with random effects

This paper deals with testing the functional form of the covariate effects in a Cox proportional hazards model with random effects. We assume that the responses are clustered and incomplete due to right censoring. The estimation of the model under the null (parametric covariate effect) and the alternative (nonparametric effect) is performed using the full marginal likelihood. Under the alternative, the nonparametric covariate effects are estimated using orthogonal expansions. The test statistic is the likelihood ratio statistic, and its distribution is approximated using a bootstrap method. The performance of the proposed testing procedure is studied through simulations. The method is also applied on two real data sets one from biomedical research and one from veterinary medicine.     

Semiparametric regression of multidimensional genetic pathway data: least-squares kernel machines and linear mixed models

We consider a semiparametric regression model that relates a normal outcome to covariates and a genetic pathway, where the covariate effects are modeled parametrically and the pathway effect of multiple gene expressions is modeled parametrically or nonparametrically using least-squares kernel machines (LSKMs). This unified framework allows a flexible function for the joint effect of multiple genes within a pathway by specifying a kernel function and allows for the possibility that each gene expression effect might be nonlinear and the genes within the same pathway are likely to interact with each other in a complicated way. This semiparametric model also makes it possible to test for the overall genetic pathway effect. We show that the LSKM semiparametric regression can be formulated using a linear mixed model. Estimation and inference hence can proceed within the linear mixed model framework using standard mixed model software. Both the regression coefficients of the covariate effects and the LSKM estimator of the genetic pathway effect can be obtained using the best linear unbiased predictor in the corresponding linear mixed model formulation. The smoothing parameter and the kernel parameter can be estimated as variance components using restricted maximum likelihood. A score test is developed to test for the genetic pathway effect. Model/variable selection within the LSKM framework is discussed. The methods are illustrated using a prostate cancer data set and evaluated using simulations.     

Patient-specific dose finding based on bivariate outcomes and covariates

SUMMARY: A Bayesian sequential dose-finding procedure based on bivariate (efficacy, toxicity) outcomes that accounts for patient covariates and dose-covariate interactions is presented. Historical data are used to obtain an informative prior on covariate main effects, with uninformative priors assumed for all dose effect parameters. Elicited limits on the probabilities of efficacy and toxicity for each of a representative set of covariate vectors are used to construct bounding functions that determine the acceptability of each dose for each patient. Elicited outcome probability pairs that are equally desirable for a reference patient are used to define two different posterior criteria, either of which may be used to select an optimal covariate-specific dose for each patient. Because the dose selection criteria are covariate specific, different patients may receive different doses at the same point in the trial, and the set of eligible patients may change adaptively during the trial. The method is illustrated by a dose-finding trial in acute leukemia, including a simulation study.     

Constrained parametric model for simultaneous inference of two cumulative incidence functions

We propose a parametric regression model for the cumulative incidence functions (CIFs) commonly used for competing risks data. The model adopts a modified logistic model as the baseline CIF and a generalized odds‐rate model for covariate effects, and it explicitly takes into account the constraint that a subject with any given prognostic factors should eventually fail from one of the causes such that the asymptotes of the CIFs should add up to one. This constraint intrinsically holds in a nonparametric analysis without covariates, but is easily overlooked in a semiparametric or parametric regression setting. We hence model the CIF from the primary cause assuming the generalized odds‐rate transformation and the modified logistic function as the baseline CIF. Under the additivity constraint, the covariate effects on the competing cause are modeled by a function of the asymptote of the baseline distribution and the covariate effects on the primary cause. The inference procedure is straightforward by using the standard maximum likelihood theory. We demonstrate desirable finite‐sample performance of our model by simulation studies in comparison with existing methods. Its practical utility is illustrated in an analysis of a breast cancer dataset to assess the treatment effect of tamoxifen, adjusting for age and initial pathological tumor size, on breast cancer recurrence that is subject to dependent censoring by second primary cancers and deaths.     

Using sufficient direction factor model to analyze latent activities associated with breast cancer survival

High-dimensional gene expression data often exhibit intricate correlation patterns as the result of coordinated genetic regulation. In practice, however, it is difficult to directly measure these coordinated underlying activities. Analysis of breast cancer survival data with gene expressions motivates us to use a two-stage latent factor approach to estimate these unobserved coordinated biological processes. Compared to existing approaches, our proposed procedure has several unique characteristics. In the first stage, an important distinction is that our procedure incorporates prior biological knowledge about gene-pathway membership into the analysis and explicitly model the effects of genetic pathways on the latent factors. Second, to characterize the molecular heterogeneity of breast cancer, our approach provides estimates specific to each cancer subtype. Finally, our proposed framework incorporates sparsity condition due to the fact that genetic networks are often sparse. In the second stage, we investigate the relationship between latent factor activity levels and survival time with censoring using a general dimension reduction model in the survival analysis context. Combining the factor model and sufficient direction model provides an efficient way of analyzing high-dimensional data and reveals some interesting relations in the breast cancer gene expression data.